Pge1 oximes

ABSTRACT

THE HYDROLYSIS OF OXIMES HAVING THE FORMULA   1-HO,2-(CH3-(CH2)4-CH(-OH)-CH=CH-),3-(HOOC-(CH2)6-),4-   (R-O-N=)CYCLOPENTANE   R=H, ALKYL, ALKENYL, CYCLOALKYL, HALOALKYL OR ARALKYL   THE ESTERS AND/OR SALTS THEREOF, YIELDS THE CORRESPONDING HYPOTENSIVE AND LUTEOLYTIC KETONE, I.E. PROSTAGLANDIN E1.

United States Patent Ofice 3,657,328 PGE, OXIMES Neville Finch, West Orange, N.J., assignor to Ciba- Geigy Corporation, Summit, NJ.

No Drawing. Continuation-impart of application Ser. No. 704,533, Feb. 12, 1968, now Patent No. 3,532,721, which is a continuation-in-part of application Ser. No. 640,374, May 22, 1967, now Patent No. 3,538,120. This application May 22, 1970, Ser. No. 39,870

Int. Cl. C07c 131/08 US. Cl. 260-514 R 6 Claims ABSTRACT OF THE DISCLOSURE The hydrolysis of oximes having the fonrnula CH=CH |iH(C 2)l- H3 (CHz)u-COOH R-O- R=H, alkyl, alkenyl, cycloalkyl, haloalkyl or aralkyl the esters and/or salts thereof, yields the corresponding hypotensive and luteolytic ketone, i.e. prostaglandin E CROSS-REFERENCES TO RELATED APPLICATIONS This is a continuation-in-part of application Ser. No. 704,533, filed Feb. 12, 1968 now Pat. No, 3,532,721,

which in turn is a continuation-in-part of application Ser. No. 640,374, filed May 22, .1967, now Pat. No. 3,538,120.

SUMMARY OF THE INVENTION The present invention concerns and has for its object the provision of the w-[2a-(3-hydroxy-1-octenyl)-3;3-hydroxy-S-oxo-cyclopentyl]-heptanoic acid of Formula I wherein X stands for 0x0, its esters or salts, by cleavage of the corresponding oximes of Formula I in which X stands for a free or aliphatically etherified hydroxyamino group, of methods for their preparation, as well as of new intermediates. The optically active acid of Formula I, in which X stands for 0x0, is the known prostaglandin E or PG E which is a potent hypotensive, pregnancy terminating or labor inducing agent in mammals.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The O-substituents of an etherified hydroxyimino group X are, for example, lower alkyl, such as methyl, ethyl, nor i-propyl, -butyl, -pentyl, -hexyl or -heptyl; lower alkenyl, such as allyl or methallyl; cycloalkyl or cycloalkyl-lower alkyl containing preferably 3 to -6 ringand 1 to 4 chain-carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl; cyclopropylmethyl, cyclopentyhmethyl, cyclohexylmethyl, 1- or Z-cyclopentylethyl or 1-, 2- or 3- cyclohexyl-propyl. These aliphatic radicals are unsubstituted or substituted, for example, by esterified hydroxy groups, preferably one or more than one halogen atom, e.g. chloro, bromo or iodo, being separated from the oxygen atom of the oxime group by at least 2 carbon atoms, and/or an aromatic radical, preferably phenyl or 3,057,328 Patented Apr. 18, 1972 phenyl substituted by one or more than one, especially one or two, of the same or different substituents, such as lower alkyl, e.g. methyl, ethyl, nor i-propyl or -butyl, lower alkoxy, e.g. methoxy, ethoxy, nor i-propoxy or -butoxy, lower alkylenedioxy, e.g. methylenedioxy, 1,1- or 1,2 ethylenedioxy, halogeno, e.g. rfluoro, chloro, bromo or iodo, trifluoromethyl, nitro or amino, such as di-lower alkylamino, e.g. dimethylamino or diethylamino. "Preferred substituted aliphatic radicals are 2-(chloro, bromo or iodo)-ethyl, -propyl or -butyl, 2,2-dichloroethyl, -propyl or -butyl, 3,3,3-trichloroethyl, 3-(chloro or bromo)-propyl or -butyl, 4-(chloro or bromo)-butyl, R methyl, 1- or Z-R-ethyl, in which R stands for phenyl, (lower alkyl)-phenyl, (lower alkoxy)-phenyl, (lower alkylenedioxy)-phenyl, (halogeno)-phenyl, (trifluoromethyl) phenyl (nitro) phenyl or (di lower alkylamino)- phenyl. The term lower, referred to above and hereinafter in connection with organic radicals or compounds respectively, defines such with up to 7, preferably up to 4, carbon atoms.

The esters of the acids of Formula I, in which X stands for 0x0 or said hydroxyimino groups, are more particularly those of alcohols, e.g. of the above-mentioned lower aliphatic or araliphatic alcohols, which may etherify the hydroxyimino group. Preferred are esters of lower alka nols. Salts of said acids are more particulaly those of alkali or alkaline earth methls, e.g. sodium, potassium, magnesium or calcium salts, or ammonium salts derived from ammonia or amines, preferably aliphatic amines, such as mono-, dior tri-lower alkylarnines, e.g. methylamine, ethylamine, diethylamine or triethylamine, or heterocyclic bases, e.g. pyrrole, pyrrolidine, pyridine, lutidine, piperidine, piperazine and the like, or therapeutically useful bases, such as 2-heptamethylene-ethylguanidine, l hydrazinoor 1,4 dihydrazino phthalazine, 3- methylamino isocamphane, N -methyl-N-2-propynyl-benzylamine, glucosamine, glutamine, galactamine, epinephrine, norepinephrine, ephedrine, phenylephrine, procaine and the like.

Particularly useful starting materials in the process of the invention are those of Formula I, wherein X stands for hydroxyimino, lower alkoxyirnino, 2-(mono-, dior trihalogeno)-lower alkoxyimino, and the lower alkyl esters of these compounds.

Especially valuable are the compounds of Formula I, in which X stands for hydroxyimino, methoxyimino or 2- -(chloro, bromo or iodo)-ethoxyimino.

The cleavage of said oximes, according to the present invention, is advantageously carried out by hydrolysis in the presence or absence of a hydroxylamine acceptor, preferably under mild conditions. In said hydrolysis advantageously aqueous acids are used, for example, mineral acids or strong organic acids, such as hydrohalic acids, sulfuric or perchloric acid; carboxylic or sulfonic acids, such as trifiuoroacetic or p-toluene sulfonic acid. Hydroxylamine acceptors are preferably oxo-compounds, which at the same time also may serve as hydrolytic agent (for example ketoacids) e.g. formaldehyde, acetone or levulinic acid; or nitrous acid and the like.

The cleavage of the oximes can also be carried out with the aid of reducing agents. For example, the 2-haloalkoxyimino compounds can be converted either into the O-unsubstituted oxime or directly into the ketone, by reductive cleavage or hydrolysis respectively. Said cleavage, for example, of the 2-bromoalkoxyimino compounds, is advantageously carried out with the use of metals, such as magnesium or preferably zinc, or reductive metal salts, such as chromium II salts, e.g. chromium II acetate, whereby unsaturated aliphatic or araliphatic hydrocarbons are generated. The resulting O-unsubstituted oximes can easily be cleaved under mild conditions, for example with the use of aqueous carboxylic acids, such as acetic acid, advantageously in the presence of nitrous acid. The reductive hydrolysis is advantageously carried out with the 2-iodoalkoxyimino compounds and chromium II salts, for example chromium II acetate in moist dimethylsulfoxide, whereby an intermediate organochromium compound is formed, which functions as an internal Lewis acid, to yield prostaglandin E directly.

The starting material used in the present process, as well as the intermediates in its synthesis, i.e. the compounds of the Formulae I (X=a hydroxyimino group) and III to XIII shown below, are new and are intended to be included within the scope of the present invention. They can be prepared according to the following formulae scheme:

o 0 OR AgOOC-R" I Br-N cam o 001V RC 0 o o 0 OR (CH2)6COOR' 0 (III) na' sio o 0 OR a; nysiol III H3O (CHa)t-COOR 0 (IV) R "Si0 o o 0 R Ni IV H;

V NHlOR onmooon' RON v1) coon VI base (cum-coon R O-N VII coon VII O Q \l 0 cum-000a 1% RON (VIII 0 ,0 onion VIII NaBHI x cunt coon 1H) v N (1X) prto IX Hz i cam-coon R=lower alkyl or Z-haloalkyl; R'=H or lower alkyl.

In the above reactions, any resulting ester may be hydrolyzed, for example, with the use of inorganic bases, such as aqueous solutions of alkali metal hydroxides, carbonates or bicarbonates, or trans-esterified, advantageously in the presence of small amounts of acids. The acids obtained may be esterified in the usual manner, for example, with alcohols in the presence of acids, with reactive esters or preferably diazo-compounds, or salified with any suitable base or ion exchanger. Any salt obtained may be converted into the free acid or another salt according to known methods.

Said reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing agents and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures, at atmospheric or superatmospheric pressure.

The invention further includes any variant of the above process, in which an intermediate product obtainable at any stage thereof is used as starting material and at any remaining steps are carried out, or the synthesis is discontinued at any stage thereof, or in which a starting material or intermediate respectively is formed under the reaction conditions, or in which a reaction component is used in the form of a salt or another reactive derivative.

Compounds of the invention and/or starting materials (for example special 0 (2 haloalkyl)-hydroxylamines used in the preparation of the intermediates VI), that are mixtures of isomers, may be separated into single isomers by methods in themselves known. For example, compounds that contain one or more asymmetrical carbon atoms may be in the form of racemate mixtures, pure racemates, or optical antipodes. Mixtures of racemates can be resolved into pure racemates by virtue of the physicochemical differences between the components, for example, by chromatography and/or fractional crystallization. Racemic products can be resolved into optical antipodes, for example, by reaction with compounds containing no center of symmetry, separation of the diastereomeric products, such as salts or esters, and liberation of the optical active products.

The starting material used, i.e. compounds of Formula II, can be obtained according to the following formula scheme:

then (XVII) NaOR ROOC "(CHz)rCOOR (XVIII) (XVIII)+R'CO0R R000 arm-000R l OOC-R' (XIX) (XIX) (a) Br; (b) base II It is described in Pat. No. 3,466,319.

EXAMPLE 1 50 mg. of the faster moving isomer of w-[2t.'(3-hydroxy-l-octenyl) 3,8 hydroxy 5 methoxyimino-cyclopentyl]-heptanoic acid are dissolved in 4 ml. levulinic acid and 1 ml. 13% aqueous perchloric acid are added while stirring and keeping the temperature at 6. After two days the mixture is diluted with ice water, extracted with diethyl ether, the extract washed with water, dried, filtered and evaporated. The residue is allowed to stand for 5 hours in a high vacuum and is then chromatographed on infusorial earth and eluted with the upper phase obtained from the mixture consisting of: (a) 560 ml. methanol and 684 ml. water, (b) 60 ml. octanol and (c) 60 ml. chloroform, at room temperature (40 ml. of the lower phase thereof is used for impregnating the infusorial earth). The combined 5 ml. samples containing a slower moving fraction are evaporated to yield the racemic prostaglandin E of the formula It shows the relative physical data and pharmacological activity as the optically active natural product, described in U.S. Pat. No. 3,069,322.

The faster moving fraction of the eluate yields the w [20c (3 hydroxy-l-octenyl)-5-oxo-3-cyclopentenyl]- heptanoic acid of the formula OH=CHCH-(CH2) -CH I H I (CHz)a-COOH whose spectral data are identical with, and the pharmacological data correspond to those given for the optically active compound described in Biochem. Biophys. Res. Communications 21, 413 (1965).

The starting material is prepared as follows: 375 g. diethyl u-bromo-azelate are slowly added to the stirred solution of the sodium enolate, prepared from 28.5 g. sodium hydride and 131 g. ethyl cyanoacetate in ml. glycol dimethyl ether. The mixture is refluxed overnight, then the solvent is removed under reduced pressure, the residue acidified with diluted hydrochloric acid, extracted with diethyl ether, the extract dried and evaporated. The residue is distilled and the fraction boiling at -205 0.7 mm. Hg collected; it represents the triethyl a-cyanofi-carboxy-sebacate of the formula k =2225 and 1735 cm.-

0.2 g. sodium are reacted with 150 ml. dry ethanol and to the solution first 224 g. triethyl a-cyano-B-carboxy sebacate and then 34.5 g. acrylonitrile are added slowly with stirring and the mixture is allowed to stand overnight at room temperature. It is then acidified with hydrochloric acid, evaporated in vacuo and the residue, containing the 1,3-dicyan0-3,4,IO-decanetricarboxylic acid triethyl ester of the formula which is used without further purification; B.P. 18l- 183/O.l mm. Hg, k =2250 and 1735 cmf The whole amount thereof is refluxed in 1.4 liter concentrated hydrochloric acid for 24 hours, using an air condenser to permit the evaporation of the ethanol formed. The mixture is then evaporated, the residue triturated with diethyl ether and recrystallized from ethyl acetate to yield the 1,3,4,IO-decanetetracarboxylic acid of the formula melting at 143-145 The mixture of 227 g. thereof, 1 liter ethanol-benzene (3:5) and 5 ml. concentrated sulfuric acid is refluxed on a water trap overnight. Hereupon the solution is concentrated, the residue taken up in diethyl ether, the extract washed with 10% aqueous potassium carbonate, dried and evaporated. The residue is distilled and the fraction boiling at 192/ 0.13 mm. Hg collected; it represents the 1,3,4, IO-decanetetracarboxylic acid tetraethyl ester of the formula The solution of 225 g. thereof in 200 ml. dry diethyl ether is added slowly to a stirred mixture of 16 g. sodium hydride, 3 ml. ethanol and 200 ml. dry diethyl ether and the whole is stirred overnight at room temperature and for 2 additional days. Hereupon the mixture is acidified with diluted hydrochloric acid, washed with water, dried and evaporated. The residue is refluxed in diluted hydrochloric acid overnight. The mixture is then extracted with diethyl ether, the extract dried and evaporated. The residue is reesterified by refluxing it in 1 liter ethanol-benzene (3:5) and ml. concentrated sulfuric acid with a water trap. The mixture is concentrated in vacuo, the residue taken up in diethyl ether, the extract washed with aqueous potassium carbonate, dried and evaporated. The residue is distilled and the fraction boiling at 160-164/ 0.1 mm. Hg collected; it represents the 2-(6-ethoxycarbonyl-hexyl)-3-oxo-cyclopentanecarboxylic acid ethyl ester of the formula The semicarbazone thereof melts at 117, I.R.-absorption: vg =3515, 3380, 1735, 1690 and 1560 cm? The mixture of 95.5 g. thereof and 61.2 g. isopropenyl acetate is refluxed overnight in the presence of 1.0 g. ptoluene sulfonic acid. The cooled mixture is washed with 10% aqueous potassium bicarbonate, dried and evaporated. The residue is distilled and the fraction boiling at 168-175 0.1 mm. Hg collected; it represents the corresponding enol acetate.

48 g. thereof are dissolved in 100 ml. dry carbon tetrachloride, the solution is cooled to -5 and 20.6 g. bromine in 100 ml. dry carbon tetrachloride are added dropwise during one hour while stirring, and stirring is continued for /2 hour after addition. Hereupon 13.2 g. triethylamine are added, the mixture is refluxed for 2 hours and allowed to stand at room temperature overnight. The precipitate formed is removed by filtration, the filtrate evaporated in vacuo, the residue distilled and the fraction boiling at 153-154/0.1 mm. Hg collected; it represents the 2-(6-ethoxycarbonyl-hexyl)-3-oxo-1-cyclopentenecarboxylic acid ethyl ester of the formula The semicarbazone thereof melts at 87-88"; UV.- absorption: x =298 m I.R.-absorption:

.gg9 =351o, 3370, 1720, 1690, and 1560 cm.''

2.27 g. thereof are disoslved in 25 ml. methanol and 25 ml. 10% aqueous potassium carbonate are added. The mixture is refluxed for 1% hours, cooled and extracted with diethyl ether. The aqueous solution is cooled in an ice bath, acidified with concentrated hydrochloric acid and extracted with diethyl ether. The extract is dried, evaporated and the residue recrystallized from benzene to yield the 2-(6-carboxy-hexyl)-3-oxo-l-cyclopentene-carboxylic acid melting, after recrystallization from water, at 9596.

43.0 g. thereof are dissolved in the minimum amount of diethyl ether, and to the stirred solution ethereal diazomethane is added dropwise until the yellow color persists. The mixture is evaporated in vacuo, the residue distilled and the fraction boiling at 146/0.1 mm. Hg collected; it represents the 2-(p-methoxycarbonyl-hexyl)-3-oxo-1-cyclopentene-carboxylic acid methyl ester.

The mixture of 14.7 g. thereof, 100 ml. carbon tetrachloride and 11.56 g. N-bromo-succinimide is refluxed for two hours while stirring. It is then filtered, the filtrate evaporated in vacuo and the residue dissolved in 50 ml. acetic acid. To the solution 13.0 g. silver acetate are added and the mixture is stirred and refluxed for one hour under nitrogen. It is poured into excess cold 10% aqueous sodium bicarbonate and the mixture is extracted with diethyl ether. The extract is dried, evaporated, the residue distilled and the fraction boiling at l69-170/ 0.01 mm. Hg collected; it represents the 2-(6-methoxycarbonyl hexyl)-3-oxo-5-acetoxy-l-cyclopentene-carboxylic acid methyl ester of the ofrmula GH -coo The solution of 10.1 g. thereof in 200 ml. 1.7 N-methanolic hydrochloric acid is allowed to stand at room temperature for 4 hours and then evaporated in vacuo. The residue is taken up in diethyl ether, the solution washed with water, dried, filtered and evaporated. The residue is chromatographed on 300 g. silica gel and eluted with ethyl acetate-methylene chloride (1:4) and (3:2). The latter eluate yields the desired 2-(6-methylcarbonyl-hexyl) 3 oxo-S-hydroxy-l-cyclopentene-carboxylic acid methyl ester, boiling at 156158/0.01 mm. Hg. (Its semicarbazone melts at l40-l41 after recrystallization from aqueous methanol.)

3.0 g. thereof are dissolved in ml. diethyl ether and 10 ml. trimethylsilyl chloride are added dropwise while stirring, followed by 15 ml. triethylamine. After stirring for /2 an hour at room temperature, the mixture is filtered and the filtrate evaporated in vacuo. The residue is chromatographed on 250 g. silica gel and eluted with ethyl acetate-methylene chloride (1:9), to yield the 2-(6- methoxycarbonyl-hexyl)-3-oxo 5 trimethylsiloxy-l-cyclopentene-carboxylic acid methyl ester of the formula (CHmSiO GHzh-COOCH;

, pentane-carboxylic acid methyl ester of the formula (CH;) SiO COOCHa I CH2)0COOCH; O

which shows in the UN. spectrum only end-absorption; M.P. 22-24".

The mixture of 3.5 g. thereof, 30 ml. pyridine and 8.0 g. O-methyl-hydroxylamine hydrochloride, is allowed to stand at room temperature for 24 hours. It is then evaporated in vacuo, the residue taken up in water, the mixture extracted with diethyl ether, the extract dried, filtered and concentrated. After cooling the Zoe-(6- methoxycarbonyl-hexyl)-3-methoxyimino 50c hydroxycyclopentane-carboxylic acid methyl ester of the formula COOCH;

crystallizes and melts, after recrystallization from a large volume hexane, at 46-47. It shows in the N.M.R. spectrum peaks at 159, 166, 219, 224 and 230 c.p.s., and exhibits hypotensive effects.

In the analogous manner the Zu-(G-methoXy-carbonylhexyl)-3-hydroxyirnino 50c hydroxy-cyclopentane-carboxylic acid methyl ester is obtained, melting at 9798 after recrystallization from benzene-hexane.

15.8 g. of the methyloxime are dissolved in 450 ml. methanol and 450 ml. 10% aqueous potassium carbonate are added. The mixture is refluxed for 2 hours, cooled and extracted with diethyl ether. The aqueous layer is acidified with ice cold hydrochloric acid, saturated with ammonium sulfate and extracted with diethyl ether. The extract is dried, filtered and to the filtrate ethereal diazomethane is added until the yellow color persists. After standing for 1 /2 hours at room temperature, the mixture is Washed with 10% aqueous potassium bicarbonate, dried and evaporated to yield the 2fi-(6-methoxycarbonylhexyl) 3 methoxyimino-5fi-hydroxy-cyclopentane-carboxylic acid methyl ester of the formula 01130- showing in the N.M.R. spectrum peaks at 229, 223 and 218 c.p.s. In the thin layer chromatogram (silica gel), eluted by ethyl acetate-chloroform 1:1, it travels faster than its above-described epimer.

The mixture of 3.05 g. thereof, 175 ml. methylene chloride, 1.3 g. dihydropyrane and 75 mg. picric acid is allowed to stand at room temperature for 24 hours. Hereupon it is evaporated in vacuo, the residue taken up in 40 m1. diethyl ether, the solution washed with aqueous potassium bicarbonate and evaporated. The residue is chromatographed on 100 g. silica gel and eluted with ethyl acetate-methylene chloride (1:19) and (1:9). The latter eluate yields the 2p-(6-methoxycarbonylhexyl) 3 methoxyimino-Sfl-(2-tetrahydropyranyloxy)- cyclopentane-carboxylic acid methyl ester, of the formula pooch,

(CH2) s-C OO C H; CHsO-BL (CH2)5C O O C2115 CH3O- showing in the N.M.R. spectrum peaks at 280, 247 and 229 c.p.s.

To the stirred mixture of 0.5 g. thereof, 6 ml. dimethyl sulfoxide and 6 ml. benzene, the mixture of 0.15 ml. pyridine and 0.08 ml. trifluoroacetic acid is added, followed by 1.8 g. 1-cyolohexyl-3-(2-morpholino-ethyl) carbodiimide metho-p-toluene sulfonate. The mixture is allowed 10 to stand for 24 hours at 4 and is then shaken with diethyl ether and ice water. The organic layer is dried, filtered and evaporated to yield the 25-(6-ethoxycarbonylhexyl)-3-methoxyimino 5,3 (Z-tetrahydropyranyloxy)- cyclopentane-aldehyde of the formula CH2)6OO0C2H5 CHsO-N showing in the N.M.R. spectrum peaks at 536, 277, 247 and 229 c.p.s.

The solution of 0.4 g. thereof in 5 ml. diethyl ether is combined with the tri-n-butyl-phosphorane obtained from 350 mg. 1-chloro-2-heptanone and 410 mg. tri-n-butylphosphine in refluxing chloroform, treatment of the resulting phosphonium compound with ZN-aqueous sodium hydroxide, distillation and collection of the fraction boiling at 144-146/ 0.02 mm. Hg. The mixture is allowed to stand at room temperature for minutes, and then evaporated. The residue is chromatographed on 25 g. silica gel and eluted with ethyl acetate-methylene chloride (1:19), to yield the w-[2u-(3-oxo-l-octenyl) 3p (2-tetrahydropyranyloxy)-5-methoxyimino cyclopentyl]-heptanoic acid ethyl ester of the formula I (CIIQP-COOCzH; C1130- showing in the N.M.R.-spectrum peaks at 405, 372, 277, 247, 229 and 53 c.p.s.

The mixture of 0.29 g. thereof, 25 ml. methanol and 5 drops N-hydrochloric acid, is stirred at room temperature for 2 /2 hours and evaporated in vacuo. The residue is taken up in diethyl ether, the solution washed with water, dried, filtered and evaporated. The residue is chromatographed on 8 g. silica gel and eluted with ethyl acetate-methylene chloride (1:19) and 1:4). The latter eluate yields the w-[2a-(3-oxo-1-octenyl) 3,8 hydroxy- S-methoxyiminocyclopentyl]-heptanoic acid ethyl ester of the formula showing in the N.M.R. peaks at 405, 372, 247, 229 and 53 c.p.s. and in the U.V.-spectn1m a A =225 m (6 15,- 200).

The corresponding free acid is obtained from 52 mg. thereof, 15 ml. methanol and 3 ml. 10% aqueous potassium carbonate While stirring overnight at room temperature. The mixture is then diluted with water, acidified with hydrochloric acid, saturated with ammonium sulfate and extracted with diethyl ether. The extract is dried, filtered and evaporated to yield said heptanoic acid derivative, which is recrystallized from pentane-diethyl ether While cooling in an ice salt bath; it melts at room temperature.

To the solution of 0.2 g. thereof in 20 ml. 1,2-dimethoxyethane, 0.4 g. lithium 3-tert. butoxy-aluminum hydride are added portionwise and the mixture stirred at room temperature for 4 hours. It is evaporated in vacuo below 35 the residue taken up in 10 ml. Water, the solution adjusted to a pH of 3-4 with cold N-hydrochloric acid and extracted with diethyl ether. The extract is dried, filtered, evaporated and the residue chromatographed on EXAMPLE 2 30 mg. of the w-[2a-(3-hydroxy-1-octenyl)-3/3-hydroxy- S-methoxyimino-cyclopentyl]-heptanoic acid are dissolved in 1 ml. of a 9:1 mixture of freshly distilled levulinic acid and 13% aqueous perchloric acid, and the solution is stirred for 2 days at 4. It is diluted with methylene chloride, the mixture washed with cold brine and evaporated. The residue is put onto a column, containing 5 g. silicic acid (Mallinckrodt material, screened through a sieve with 0.125 to 0.15 mm. openings, well washed with methanol, acetone and diethyl ether, dried and reactivated at 120 overnight) which is eluted first with 1% methanol in chloroform to yield as the first fraction the w-[2ot-(3-hydroxy 1 heptenyl)-5-oxo-3-cyclopentenyl]- heptanoic acid, followed by a second fraction of levulinic acid, which was not removed by the previous washing procedure. With 2.5% methanol in chloroform, a trace of starting material is eluted and with 3.5% methanol in chloroform the desired racemic prostaglandin E is eluted, showing in the N.M.R.-spectrum signals at 336 (triplet) and 243 c.p.s. (multiplet); it is identical with the product obtained according to Example 1.

The starting material is prepared as follows: 790 mg. of the w- [2u-(3-oxo-1-octenyl -3/3-(Z-tetrahydropyranyloxy)-5-methoxyimino-cyclopentyl]-heptanoic acid ethyl ester are dissolved in 65 ml. 95% aqueous ethanol, 1.5 g. sodium borohydride are added, and the mixture is stirred under nitrogen for 7 5 minutes at room temperature. It is diluted with ice water, extracted with diethyl ether, the extract dried, filtered and evaporated. The residue is chromatographed on silica gel and eluted with ethyl acetatemethylene chloride (1:9) to yield the w-[Za- (S-hydroxy-l-octenyl) 3B (Z-tetrahydropyranyloxy)-5- methoxyimino-cyclopentyl]heptanoic acid ethyl ester of the formula showing in the I.R.-spectrum (liquid film) a broad absorption band at 3,400 cm.- (but no band in the U.V.- spectrum at 255 mg).

410 mg. thereof are dissolved in 60 ml. methanol, 1 ml. N-hydrochloric acid is added and the mixture stirred at room temperature for 3 /2 hours. It is diluted with ice water, extracted with diethyl ether, the extract dried, filtered and evaporated. The residue is subjected to preparative thin layer chromatography on alumina G.F. plates (1 mm. thick) and eluted with cyclohexane-dioxan-ethylacetate (7:2.5:0.5) to produce 3 bands of material. The fastest moving band can be detected by UV. absorption and the slower moving hands by a phosphomolybdic acid spray. The slowest moving band is eluted with methanol and the eluate evaporated. 33 mg. of the residue obtained are dissolved in 10 ml. methanol, ml. of aqueous potassium carbonate are added and the mixture is refiuxed for 1 hour. After cooling it is washed with diethyl ether, the aqueous layer acidified with 2 N hydrochloric acid and extracted with diethyl ether. The extract is dried, filtered and evaporated and the residue recrystallized from aqueous methanol, to yield the w-[2a-(3-hydroxy-1-octenyl)-3/3-hydroxy 5 methoxyimino-cyclopentyl]-heptanoic acid, melting at 97-99"; it is identical with that obtained according to Example 1 and shows in the LR. and N.M.R.-spectra the same signals as the methyloxime of natural prostaglandin E Both compounds also have the same mobility in thin layer chromatography on silica gel, when eluted with ch10roform-methanol-acetic acidwater (90:6:1:0.7).

EXAMPLE 3 mg. w-[2a-(3-hydroxy-1-octenyl)-3;8-hydroxy-5-methoxyimino-cyclopentyl]-heptanoic acid (prostaglandin E methyloxime) are dissolved in 1 ml. 80% aqueous pyruvic acid of 4 While stirring and the solution is allowed to stand for 3 days at 4. It is put onto a column of 10 g. silicic acid kept at 4 (Mallinckrodt material screened through a sieve with 0.125 to 0.15 mm. openings, washed with methanol, acetone and diethyl ether, dried and reactivated at 130 overnight) which is eluted first with 225 ml. 1% methanol in chloroform to yield the w-[Zot- 3-hydroxy-1-heptenyl) -5-oxo-3-cyclopentenyl] -heptanoic acid and pyruvic acid. With 2 and 3% methanol in chloroform, 40 mg. of a mixture of said ketone and starting material is obtained and with 4% methanol in chloroform 18 mg. pure, racemic prostaglandin E is obtained, which is identical with the product obtained according to Example 2.

EXAMPLE 4 To the solution of 96 mg. w-[2a-(3-hydroxy-1-octenyl)- 3/8-hydroxy 5 (2-bromoethoxyimino)-cyclopentyl]-heptanoic acid is 15 ml. methanol, 300 mg. zinc dust are added and the mixture refluxed overnight. After cooling, the mixture is filtered through infusorial earth and the filtrate evaporated in vacuo. The residue is taken up in ice cold N-hydrochloric acid and the mixture extracted with diethyl ether. The extract is dried, filtered and evaporated. The residue is taken up in 10 ml. aqueous acetic acid, the solution cooled to 5-10" and 7 ml. 10% aqueous sodium nitrite are added while stirring. After stirring for 3 hours at 10, the solution is saturated with sodium chloride, the mixture extracted with ethyl acetate, the extract dried, filtered and evaporated. The residue is chromatographed on freshly prepared silicic acid and eluted with 3% methanol in chloroform, to yield racemic prostaglandin E melting at 112-113".

The starting material is prepared as follows: To the solution of 2.8 g. 2a-(6-methoxycarbonylhexyl)-3-oxo- 5-trimethylsilyloxy-cyclopentane-carboxylic acid methyl ester in 50 ml. pyridine, 5.8 g. O-(2-bromoethyl)-hydroxylamine hydrobromide are added and the mixture stirred at room temperature for 5 hours. It is evaporated in vacuo below 45 the residue taken up in water, the mixture extracted with diethyl ether, the extract washed with water, N hydrochloric acid and water, dried and evaporated, to yield the 2a-(6-methoxycarbonylhexyl)-3- (2-bromoethoxyimino) 5o: hydroxy-cyclopentane-carboxylic acid methyl ester, showing in the IR. spectrum bands at 1173, 1205, 1660, 172 8, 1741 and 348 cm.-

The mixture of 3.3 g. thereof, ml. methanol and 125 ml. 10% aqueous potassium carbonate is refluxed for 4% hours and allowed to stand at room temperature overnight. It is washed with diethyl ether, the aqueous layer acidified with concentrated hydrochloric acid, saturated with sodium chloride and extracted with diethyl ether. The extract is dried, filtered, evaporated and the residue taken up in 15 ml. diethyl ether. To the solution, ethereal diazomethane is added while stirring until the yellow color persists. After 1 hour, the mixture is evaporated in vacuo, the residue taken up in diethyl ether, the solution washed with 10% aqueous potassium bicarbonate, dried and evaporated, to yield the 2 8-(6-methoxycarbonylhexyl) 3 (2-bromoethoxyimino)-5fi-hydroxy-cyclopentane-carboxylic acid methyl ester.

To the mixture of 680 mg. thereof, 40 ml. methylene chloride and 12 ml. dihydropyrane, 25 mg. picric acid are added and the mixture stirred overnight at room temperature. It is evaporated in vacuo, the residue taken up in diethyl ether, the solution washed with Water and 10% aqueous potassium bicarbonate, dried and evaporated, to yield the 2B (6 methoxycarbonylhexyl)-3-(2-bromoethoxyimino) /3 (Z-tetrahydropyranyloxy)-cyclopentanecarboxylic acid methyl ester, showing in the IR. spectrum bands at 1033, 1172, 1200, 166-5, 1725 and 1747 cmr To the solution of 1.1 g. thereof in 50 ml. anhydrous ethanol, 2.3 g. sodium borohydride are added while stirring. After stirring for 2 /2 hours at room temperature, the mixture is poured into ice water and extracted with diethyl ether. The extract is washed with Water, dried, filtered and evaporated. The residue is chromatographed on 45 g. silica gel, eluted first with twelve 75 ml. portions ethyl acetate in methylene chloride, seven 75 ml. portions 20% ethyl acetate in methylene chloride and 1.2 liter 40% ethyl acetate in methylene chloride, which fraction is collected and evaporated, to yield the w-[2a-hydroxymethyl-3 3-(2- tetrahydropyranyloxy) 5 (2-bromoethoxyimino)-cyclopenty1]-heptanoic acid methyl ester, showing in the IR. spectrum bands at 1018, 1040, 1202, 1650, 1722, 1742 and 3450 cm.-

To the ice-cold solution of 730 mg. thereof in 25 ml. benzene and 25 ml. dimethylsulfoxide, 0.56 ml. pyridine, 0.43 ml. trifluoroacetic acid and 7.77 g. l-cyclohexyl-3-(2- morpholinoethyl)-carbodiimide metho-p-toluenesulfonate are added in this order and the mixture stirred at 4 for 5 days. It is poured into ice water, extracted with diethyl ether, the extract washed with water, dried, filtered and evaporated, to yield the 2B-(6-methoxycarbonylhexyl)-3- (2 bromoethoxyimino)-5fi-(Z-tetrahydropyranyloxy)-cyclopentanealdehyde, showing in the IJR. spectrum bands at 1025, 1040, 1202, 1655, 1720, 1742 and 2715 cmf To the solution of 680 mg. thereof in 25 ml. diethyl ether, 900 mg. tri-n-butyl-(2-oxo-n-heptylidene)-phosphorane in 50 ml. diethyl ether are added and the mixture stirred at room temperature overnight. It is evaporated in vacuo, the residue chromatographed on 47 g. silica gel and the last 11 of 12 fractions obtained with 75 ml. 10% ethyl acetate in methylene chloride each, collected and evaporated, to iyeld the w-[2a-(3-oxo-1-octenyl)-3B-(2-tetrahydropyranyloxy) 5-(2-bromoethoxyimino)-cyclopentyl]- heptanoic acid methyl ester, showing in the LR. spectrum bands at 1030, 1040, 1202, 1635, 1655, 1675, 1697 and 1737 (XXL-1.

To the solution of 720 g. thereof in 50 ml. 95% aqueous ethanol, 1.5 g. sodium borohydride are added and the mixture stirred for 45 minutes at room temperature. It is diluted with ice water, extracted with diethyl ether, the extract washed with ice water, dried, evaporated and the residue chromatographed on 21 g. silica gel. The column is eluted with nine 50 ml. portions 10% ethyl acetate in methylene chloride, eight portions 15% ethyl acetate in methylene chloride and seven such portions ethyl acetate in methylene chloride, and the 2nd to 18th fraction collected, to yield the w-[Za-(3-hydroxy-1-octenyl)-3B-(2- tetrahydropyranyloxy) 5 (2-bromoethoxyimino)-cyclopenty1]-heptanoic acid methyl ester, showing in the LR. spectrum bands at 1030, 1040, 1205, 1670, 1730 and 3420 cm."

The mixture of 605 mg. thereof, 50 ml. methanol and 10 drops iN-hydrochloric acid is stirred at room temperature 14 60% ethyl acetate in methylene chloride, and fractions 27 to 48 are combined and evaporated, to yield the w-[2a-(3- hydroxy-l-octenyl)-3B-hydroxy 5 (2 bromoethoxyimino)-cyclopentyl]-heptanoic acid methyl ester, showing in the LR. spectrum bands at 1020, 1075, 1170, 1200, 1650, 1730 and 3375 cmf The mixture of 280 mg. thereof, 50 ml. methanol and 50 ml. 10% aqueous potassium carbonate is refluxed for 2 hours, cooled and diluted with water. It is washed with diethyl ether, acidified with 2 N hydrochloric acid, saturated with sodium chloride and extracted with diethyl ether. The extract is dried and evaporated, to yield the corresponding free acid, which is used as such without further purification.

EXAMPLE 5 To the solution of 100 mg. w-[2oz-(3-hYdl'0XY-l-0Ct6flyl) 3B hydroxy 5 (2-iodoethoxyimino)-cyclopentyl]- heptanoic acid in 20 ml. moist dimethylformamide, 300 mg. freshly prepared chromous acetate are added and the mixture stirred overnight under nitrogen at 0. Hereupon it is diluted with brine, extracted with diethyl ether, the extract dried, filtered and evaporated. The residue is chromatographed on freshly prepared silicic acid and eluted with 3% methanol in chloroform, to yield racemic prostaglandin E melting at 112-113.

The starting material is prepared as follows: To the solution of 108 mg. w-[2w(3-hydroxy-1-octenyl)-3;3-h droxy 5 (2-bromoethoxyimino)-cyclopentyl]-heptanoic acid in 5 ml. dry acetone, 238 mg. sodium iodide in 10 ml. acetone are added and the mixture refluxed for 20 hours. It is evaporated in vacuo, the residue taken up in water, the mixture extracted with diethyl ether, the extract washed with water, dried and evaporated, to yield the w- [Za (3-hydroxy-1-octenyl)-3fl-hydroxy-5-(2-iodoethoxyimino) -cyclopentyl] -heptanoic acid, showing in the N.M.R. spectrum signals at 0' equals 2.10-2.48, 3.17-3.44, 4.11-4.42 and 5.42-5.76.

The above reaction of the O-(2-iodoethyl)-oxime with chromous acetate can also be carried out in moist dimethylsulfoxide and the reaction mixture allowed to stand 1 hour at room temperature, to yield said racemic prostaglandin E I claim:

1. A compound of the formula in which X is hydroxyimino, lower alkoxyimino, lower alkenyloxyimino, cycloalkoxyimino or cycloalkyl-alkoxyimino with 3 to 6 ringand 1 to 4-chain-carbon atoms, halo-lower alkoxyimino or R-lower alkoxyimino in which R is phenyl, (lower alkyl)-phenyl, (lower alkoxy)-phenyl, (lower alkylenedioxy)-phenyl, (halogeno)phenyl, (trifluoromethyl)-phenyl, (nitro)-phenyl or (di-lower alkylamino)-phenyl, and R is hydrogen or tetrahydropyranyl, or the lower alkyl esters, ammonium, alkali metal or alkaline earth metal salts thereof.

2. A compound as claimed in claim 1 and being an m- [2a-(3-hydroxy-1-octenyl) -3p-hydroxy-5-lower alkoxyimino-cyclopentyl1-heptanoic acid, or the lower alkyl esters, ammonium, alkali metal or alkaline earth metal salts thereof.

3. A compound as claimed in claim 2 and being the w- [20: (3-hydroxy-1-octenyl)-3,8-hydroxy-S-methoxyiminofor 24 hours and diluted with diethyl ether. It is poured cyclopentyl]-heptanoic acid.

onto ice water, the organic phase separated, washed with ice water, dried and evaporated. The residue is chromatographed on 15 g. silica gel and eluted with 7 35 ml. portions 5% ethyl acetate in methylene chloride, 19 portions 10%, 7 portions 20%, 7 portions 40% and 9 portions 15 5. A compound as claimed in claim 4 and being the w- [204 (3 hydroxy-l-octenyl)-3fi-hydroXy-5-(2-bromoethoxyimino) -cyclopentyl] -heptanoic acid.

6. A compound as claimed in claim 4 and being the w- 2a-(3-hydroxy 1 octenyD-3fl-hydroxy-5-(2-iodoeth0xyimino) -cyclopentyl] -heptanoic acid.

References Cited UNITED STATES PATENTS 3,504,020 3/1970 Lapidus et al. 260-514 1 6 OTHER REFERENCES Hamberg, European J. Biochem. 6, 135 (1968).

LORRAINE A. WEINBERGER, Primary Examiner 5 R. GERSTL, Assistant Examiner US. Cl. X.R.

260-2l1 R, 250 R, 268 R, 294 s, 295 s, 326.3, 340.3, 340.5, 345.7, 345.8, 468 R, 471 R, 473 A, 501.1, 501.14, 10 501.16, 501.17, 519, 520

Notice of Adverse Decision in Interference In Interference N 0. 98,412 involving Patent N 0. 3,657,328, N. Finch, PGrE OXIMES, final judgment adverse to t as to claim 1.

[Oficial Gazette November 12, 1974.]

he patentee was rendered July 18, 1974, I 

